Abstract

We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized,
polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required
discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced coagonism at
the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD.
DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ∼15% body weight loss, upon which
they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day).
The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ∼18% greater weight loss as compared with PEG-GLP-1/glucagon
alone and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect
of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following
reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 cotreatment. In summary, we report that GLP-1/glucagon coagonism
restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy
for the treatment of obesity and diabetes.